For a variety of reasons, it is desirable in the fields of pharmaceuticals, cosmetics, food, clean-tech, photography and the environment to maintain, deliver and administer (or use) active principles in a fluid state. Fluid or solubilized active principles generally act faster (eg pass more quickly through or are more quickly absorbed by membranes especially natural membranes such as skin, mucous membranes or other cell membranes) than solid or dry forms of the active principle. For specific applications such as oral administration of food supplements and pharmaceuticals, it is desirable to formulate the active principles as solutions or liquids in order to increase and/or accelerate absorption or effect and/or to enhance the control and/or predictability of absorption or effect. However, fluids and liquids tend to be less stable e.g. to light and air and tend to require special containment for transport (eg vials, tankers) and for administration (eg syringes). Further processing of solids (eg applying additional layers or coats of other materials) is generally easier than further processing of liquids which at least require a filling step into a receptacle of predefined geometry such as, for example, liquid-filled soft-gel capsules, used in the food supplements and pharmaceuticals industries, which are essentially limited in size in part by the machinery required to achieve the filling. Thus fluids are generally more difficult to formulate in discrete (individual) forms e.g. dosage forms than solids. It would therefore be desirable to have a form which presents fluid active ingredients in a way which can be easily and directly manufactured and shaped while retaining the benefits of fluids described above.
Shingel et al. (J Mater Sci: Mater Med 2008) describe a solid emulsion gel for topical delivery of hydrophilic and lipophilic drugs. A solid emulsion is normally a type of colloid in which a solid is dispersed in a liquid. However, Shingel et al. use the term to denote an oil-in-water (o/w) emulsion in which the aqueous continuous phase is a solid gel resulting from cross-linking between protein (acting also as stabilizer) and a poly ethylene glycol (PEG) derivative (activated PEG synthesised by reacting the polymer with nitrophenyl chloroformate). The researchers cast solid emulsion gel between two films to form a 1.2 mm thick sheet. According to Shingel et al., the solid aqueous phase acts like a hydrogel in its ability to absorb and then impart water e.g. when placed on skin requiring hydration. The emulsion, however, is not re-established on rehydration of the solid emulsion gel. Rather, the cross-linking has created protein-coated oil droplets (diameter range 5-20 μm) immobilized individually or as coalesced neighbouring droplets.
A particular industrial application of the present invention is in formulation for oral administration of active pharmaceuticals, nutraceuticals and food additives as well as immunomodulators, immunomodulating therapeutics and supplements.
For successful oral administration in these fields, the active principle must be in solution for local effect or systemic absorption, it must usually be stabilized before release (including protection from degrading stomach acids, pH degradation, proteolytic enzymes etc) and it must be permeable, with degrees of necessary permeability depending on whether local or systemic effect is required.
Additional requirements which pose problems in developing oral dosage forms are ease and cost of manufacture including scaleability, reproducibility and shelf-life.
If the active principle is to be delivered to the colon, as may be desirable eg. for local treatment of colonic disease, for presentation of the active principle to specific immune cells or for systemic or lymphatic absorption, additional constraints and requirements arise. Related or separate issues must be overcome if the active principle (and/or associated excipients) is desired to sequester, absorb or adsorb toxins, pollutants or other exogenous agents.
A variety of solutions to these individual problems have been identified but it is more challenging to resolve multiple such problems simultaneously in a single oral dosage form. The above described formulation issues are often greater for water-insoluble or poorly water-soluble active entities.
The above described formulation issues are often greater for water-insoluble or poorly water-soluble active entities.
Some of the issues mentioned above can be subdivided into more specific challenges. For example, the general requirement for the active principle to be in solution can be addressed by formulating it in a dissolved state and maintaining that dissolved state until release so avoiding reliance on dissolution in vivo (a “pre-dissolved” active principle). The technical challenge then becomes how to maintain the solubilized state and prevent release until the target release zone (eg colon) is reached.
A further specific need within the general requirement for the active principle to be in solution is the maintenance of the formulated active principle in a dissolved state as well as immediately after dispersion/egress from its carrier or matrix.
A particular problem in formulating active principles in a dissolved state (eg by encapsulation of solution in minispheres) arises when such dosage forms are coated with polymers intended to modify drug release characteristics. The coating may prevent full, sufficient or predictable release of active principle in the gastro-intestinal tract (GIT) or, through unpredictable swelling of or poration (pore formation) in the coating, create excess variability in release within a population.
For hydrophobic active principles, it is particularly desirable to increase water solubility or miscibility as well as to increase stability and reduce volatility. It is likewise a goal to control the availability of the active principle, particularly the bioavailability. One approach to these issues has been to use cyclodextrins, especially modified cyclodextrins as described e.g. in US 2006/0148756 A1 (Darcy et al). However, use of cyclodextrins although valuable in particular situations, can add manufacturing and quality control complexity to oral drug formulation and manufacture.
The oral delivery of combinations of otherwise physico-chemically incompatible drugs or of drugs (especially oil-soluble drugs) in soluble (“pre-solubliized”) form or to mask the unpleasant or undesirable taste or smell of active principles, has been addressed by drug delivery systems having distinct compartments within a single administrative form—see for example U.S. Pat. No. 7,431,943 (Villa et al.). In such cases, the objective is often to prevent a first drug (eg hydrophobic drug with limited stability in aqueous milieu) from coming into contact with a second drug (eg hydrophilic drug dissolved in aqueous milieu) or in the case of a single active principle to maintain it in liquid form (eg as a liquid core within a capsule) either to mask taste/smell or to ensure it is delivered in active (“pre-dissolved”) form at the desired intestinal location. In such situations, particularly when an enteric, sustained or delayed release coating is also applied to the drug form, the spatial asymmetries in the dosage form potentially lead to unpredictable release characteristics and/or unacceptable variability of drug release, bioavailability or dynamic/clinical response. In other words, distinct kinetic release characteristics apply to each compartment. This can make it difficult to achieve controlled e.g. simultaneous release of multiple drugs contained in a single form.
A related challenge in co-delivery (following co-administration) of more than one active principle is control (avoidance or enhancement, depending on the desired outcome) of interactions between the two or more active principles (or indeed, excipients) at the point(s) of release.
A further complication arising from inclusion of a liquid core within a capsule or minicapsule format is that for minicapsules to form, there is a very low threshold for surfactant in the core and this places a constraint on formulation options should it be desirable (see below) to include a surfactant in the liquid core. This is because the need for surface tension to create and maintain capsules precludes or limits use of surfactants as the reduction in surface tension caused by the surfactant in the core can destroy the integrity of the capsule or cause a more monolithic format where for example a shell or capsular layer may be desired. Thus it can be difficult to formulate liquid, emulsified or pre-solubilized active principles with surfactants which, as mentioned, may for a variety of reasons be desirable.
US Pharmacopoiea (USP), European Pharmacopoiea (EP), Japanese Pharmacopoiea (JP) and others are official public standards-setting authorities for medicines and other health care products manufactured or sold in the United States, Europe, Japan etc. Among other things, the Pharmacopoiea set recognized standards for the quality control of drug formulations to help ensure the consistency of products made for public consumption. These standards include dissolution methods, apparatus and media, often referred to as “compendial” e.g. “compendial media” meaning standard dissolution media described in USP, EP, JP etc. In the dissolution testing of sparingly water-soluble drug products, surfactants may be added to the medium to improve simulation of the environment in the GI tract—see eg. Noory et al. Dissolution Technologies, February 2000, Article 3.
The advantage of compendial methods is their relative simplicity. Their perceived disadavantage is their relatively poor predictive value in terms of assessing likely in vivo performance even with addition of surfactant to the medium. In order to enhance predictability, various non-compendial media as well as more elaborate dissolution apparatus and methods achieving improved in vivo/in vitro correlation (IVIVIC) have been developed particularly to measure colonic release—see e.g. Klein et al., J. Controlled Release, 130 (2008) 216-219.
Surfactants are also known to have been incorporated in oral pharmaceutical formulations, often as components of (usually) oil-in-water emulsions or self-emulsifying drug delivery systems (SEDDS) which are oil-phase-only formulations which spontaneously form emulsions on addition to water (sometimes therefore referred to as pre-emulsions). Where the oil droplets in these emulsions are very small, they are referred to as microemulsions (and their precursors as SMEDDS).
In general, the presence of surfactants in pharmaceutical formulations can be said to be an attempt to mimic the effect of bile salts and others, the natural surfactants synthesised in the liver and present in the GI tract. One of the main functions of bile salts is to solubilise fats in the GI tract and to facilitate their absorption into the systemic circulation and this gives an indication as to why it can be advantageous to use emulsion systems to enhance the systemic absorption of oil soluble and/or hydrophobic drugs. However, the goal of oral drug delivery is not always (or not solely) systemic absorption. If systemic absorption was not wanted, for example if local delivery with reduced, limited or negligible systemic absorption was the objective, the requirement or role, if any, for surfactants may be different.
With the rapid progress in biotechnology, peptide drugs are becoming important as therapeutic agents. A wide variety of peptides have been used as drugs, including hormones, nucleic acids, synthetic peptides, enzyme substrates and inhibitors. Although they are highly potent and specific in their physiological functions, most of them are difficult to administer orally because of the unique physicochemical properties of peptides including molecular size, poor solubility, short plasma half-life, requirement for specialised mechanisms for membrane transport and susceptibility to enzymatic breakdown (intestinal, pre-systemic and systemic). Many different approaches have been used to improve the oral absorption and enhance the bioavailability of peptide drugs. In recent years, enhanced bioavailability after oral administration has been reported by using microemulsion systems which are thermodynamically stable, isotropically clear dispersions of two immiscible liquids such as oil and water stabilized by an interfacial film of surfactant molecules. The advantages of microemulsions as drug delivery systems is the improvement of drug solubilization and protection against enzymatic hydrolysis, as well as the potential for enhanced absorption (eg from the jejunum but also the colon) due to surfactant-induced permeability changes.
However, there are a large number of technical variables which must be understood in order to design a microemulsion system suitable for a particular purpose or drug. The physicochemical properties such as drug stability, proportions of oil and water phases and the size of microemulsion droplets all affect outcome. If one or more surfactants are used, additional uncertainties arise such as the influence of surfactant to co-surfactant ratio, a consideration which is itself affected by the choice of oil in the oil phase and/or choice of surfactant or surfactant type.
A peptide drug which has been widely studied for the optimisation of microemulsion systems is ciclosporin A (International Non-Proprietary Name or INN) also known as cyclosporin(e) A.
In a microemulsion system of ciclosporin A obtained by using polyoxyethylated castor oil (CREMOPHOR® EL) as a surfactant, TRANSCUTOL® as a co-surfactant and caprylic/capric tryglyceride (CAPTEX® 355) as an oil, Gao et al (1998) in International Journal of Pharmaceutics 161 (1998) 75-86 achieved microemulsion stability with high ciclosporin A solubility, small droplet size and fast dispersion rate when selecting a CREMOPHOR® EL: TRANSCUTOL®: CAPTEX® 355 ratio of 10:5:4. No further formulation of these microemulsions was described.
UK patent application 2,222,770 (SANDOZ LTD) describes galenic formulations which contain cyclosporines in the form of microemulsions (comprising a hydrophilic phase, a lipophilic phase and a surfactant) or microemulsion preconcentrates (no hydrophilic phase) also known as premicroemulsion concentrates. Such preconcentrates spontaneously form microemulsions in an aqueous medium for example in water or in the gastric juices after oral administration. With a maximisation of systemic absorption with good inter-subject variability being the objectives, this British patent application did not describe or address the challenges and problems of formulating cyclosporine A (also spelt cyclosporin A or ciclosporin A) for delivery to the colon and/or to sections of the GIT where absorption of cyclosporin is limited.
Kim et al. (Pharmaceutical Research, Vol 18, No 4, 2001) describe a combined oral dosing regimen of premicroemulsion concentrates (as in UK patent application 2,222,770) and enteric coated solid-state premicroemulsion concentrates with the objective of achieving high systemic absorption following oral administration. In both cases, microemulsions are formed on addition to water/aqueous media. The enteric coated solid state preconcentrates are powders made by mixing the oil phase (premicroemulsion concentrate) with polymer dissolved in acetone. Removal of acetone leaves a film which is then powdered.
For colonic disease or to achieve absorption of drugs from the colon, colon-specific delivery systems must prevent the release of the drug in the upper part of the GIT yet release it on reaching the colon. Apart from pro-drugs activated by contact with the colonic milieu (eg specific bacteria or their enzymes), pure formulation approaches include pH and time-dependent polymer-mediated technologies. However, while variations in pH between the small intestine and the colon are well documented, the differences can be small and can vary between individuals. This can make pH-dependent systems unreliable in obtaining a predictable drug release profile. Time-dependent systems depend on the transit time of the delivery system in the GIT. A major limitation with these systems is that in vivo variation in the small intestinal transit time may lead to release of the bioactive (active principle) in the small intestine (too early) or in the terminal part of the colon (too late). The patho-physiological state of the individual recipient of such oral drug delivery systems also has a significant effect on the performance of these time-dependent systems—patients with irritable bowel syndrome and inflammatory bowel disease (including Crohn's disease and ulcerative colitis) often exhibit accelerated transit through the colon. Independently of these considerations, the size of the dosage form at the point of entry into the small intestine (pylorus) can have a significant effect on GI transit time and/or variability of response.
A number of other colon targeted delivery systems have been investigated. These systems include: intestinal presssure-controlled colon delivery capsules which rely on peristaltic waves occurring in the colon but not in the stomach and small intestine; combination of pH-sensitive polymer coatings (remaining intact in the upper GIT) with a coating of polysaccharides degradable only by bacteria found in the colon; pectin and galatomannan coating, degraded by colonic bacteria; and azo hydrogels progressively degraded by azoreductase produced by colonic bacteria. The preceding four systems are reviewed by Yang et al., International Journal of Pharmaceutics 235 (2002) 1-15, the entirety of which is incorporated herein by reference. Polysaccharide based delivery systems are of particular interest—see e.g. Kosaraju, Critical Reviews in Food Science and Nutrition, 45:251-258 (2005) the entirety of which is incorporated herein by reference. Nevertheless, for systems solely reliant on specific enzymatic activity in the colon, disease state can once again cause variability in the drug release profile as a result of pathological derangements in colonic flora (eg resulting from pH changes and changing amounts/activity of bacterial enzymes).
Beads of oil-in-water (o/w) emulsions are known. PCT application WO/2008/122967 (Sigmoid Pharma Limited) describes an oral composition comprising minicapsules having a liquid, semi-solid, or solid core and Figure 2 therein is a schematic of a semi-solid- or solid-filled minicapsule/minisphere wherein the active principle is solubilised or in a suspension form, with controlled release polymer coatings. Example 20 describes beads of an extruded emulsion drug suspension made from mixing an aqueous solution with an oil solution made up of squalene (a natural unsaturated hydrocarbon), Gelucire 44/14 and LABRAFIL® MS 1944 CS. The water-soluble active principle hydralazine is in the aqueous phase and the oil phase is 1.12 dry wt % of the formulation.
Dried oil-in-water (o/w) emulsions are known. U.S. Pat. No. 4,045,589 (Petrowski et al) describes a stable, dry, non-dairy fat emulsion product suitable for use as a coffee whitener. Such whiteners are prepared as dry emulsion concentrates which, on addition to an aqueous media such as coffee or tea, form a reconstituted oil-in-water emulsion which whitens and flavours the beverage. A first emulsifier is included in the liquid emulsion concentrate to promote the stability of the liquid emulsion and a second emulsifier (modified starch) is added to stabilize the emulsion through the drying step. Before drying, the fat particles in the emulsion average 1-3 μm in diameter. This liquid emulsion concentrate is dried to a moisture content not in excess of about 3%. In addition to spray drying, various other drying methods are described as possible including freeze drying, drying on heated drums etc.
U.S. Pat. No. 4,615,892 (Morehouse et al.) describes a dry imitation margarine or butter product which can be easily reconstituted to form a butter-like spread by slowly stirring the dry product into water accompanied by mixing with kitchen blenders. The dry product is made from an oil-in-water emulsion of an edible fat and a starch hydrolyzate and water. This emulsion is then dried e.g. by freeze or spray drying to reduce the moisture content to less than about 6%. During drying, agitation must be minimised and temperatures maintained above about 30° C. to prevent phase inversion prior to drying. The result is a protective film of starch hydrolyzate around the fat droplets in powder form.
U.S. Pat. No. 4,540,602 (Motoyama et al.) describes an activated pharmaceutical composition containing a solid drug that is scarcely soluble in water. When the composition is administered orally, the drug is readily absorbed to attain its high blood concentration quickly. To achieve this, the drug is dispersed in water in the presence of a water-soluble high-molecular weight substance to form finely divided particles not greater than 10 μm in diameter and then the water is removed to generate a finely divided drug coated with the water-soluble high-molecular substance in the form of a powder or granules. Emphasis is placed on achieving powders or granulates of particle size in the sub-micron range to optimise absorption from the intestinal mucosa. The water-soluble high-molecular weight substance can be a polymeric substance such as gelatin or gum arabic (Example 8 illustrates a combination of these two) or a cellulose derivative such as hydroxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, carboxymethyl cellulose sodium and the like. Where the scarcely soluble drug is first dissolved in a hydrophobic organic solvent, the dispersion can be an emulsion. The solvent can be low-boil or non-volatile in which case it remains after drying and can be orally administered without harmful effect (eg glycerides, liquid paraffin, squalane, squalene, lecithin, pristine, etc).
LiuXing et al in J. Controlled Release 93 (2003) 293-300 describe entrapment of peptide-loaded liposomes in calcium alginate gel beads ranging from 0.95 to 1.10 mm in size. The goal was to obtain a colonic release form of the entrapped peptide (bee venom) and to protect the peptide from enzymic degradation and to disrupt the mucosal membrane to increase peptide absorption. The objective was to address the low drug incorporation efficiency arising from the porosity of alginate beads.
Other problems with use of alginate results from loss of active principle during gelation due to diffusion from the concentrated gel to a less concentrated large volume cross-linking solution—see e.g. Wells et al., Eur J. of Pharmaceutics and Biopharmaceutics 65 (2007) 329-335.
Toorisaka et al. (J. Controlled Release 107 (2005) 91-96) addressed the problem of physical-chemical instability of a solid-in-oil-in water (S/O/W) emulsion. The instability led to a need for storage at low temperatures, a major impediment to pharmaceutical development. The researchers resolved this by creating a dry S/O/W emulsion in which the active principle (insulin) coated with a surfactant was the solid phase dispersed in soybean oil (oil internal phase). This was then homogenized with aqueous hydroxypropylmethylcellulose phthalate (HPMCP) to form the S/O/W emulsion. This was then dropped into hydrochloric acid to gellify the HPMCP and the resultant spherical microparticles were lyophilized to yield 1 μm diameter oil droplets coated with HPMCP. This process has many steps and is therefore complex to industrialise.